Our continued exploration of genes that impair cortical function and increase risk for developing schizophrenia (SZ) has led us to further interrogate the brain-specific KCNH2 3.1 isoform first described in Huffaker et al (Nat Med 2009). SZ is a complex psychiatric illness. Dopamine (DA), a neurotransmitter implicated in SZ, has been studied for almost 50yrs and the single target for treatment has been its D2 receptor. Current drugs rarely induce recovery, suggesting lack of specificity for its complex pathophysiology. Antipsychotics prolong Q-T wave interval and cause increases death rates. QT prolongation results from blocking the hERG1 potassium channel which regulate excitability and repolarization in neurons, cardiac, and smooth muscles. KCNH2 codes for hERG1 protein and over 300 SNPs in KCNH2 have been identified that can cause congenital or acquired long QT syndrome. KCNH2 risk alleles (TT) predict increased expression of the 3.1 isoform which has unique physiological properties and when compared with full-length KCNH2 the 3.1 mRNA levels are similar in brain but 3 times lower in heart. Apud et al (Am J Psychiatry 2012) assessed whether SNPs associated with KCNH2 3.1 expression influence therapeutic effects of antipsychotic drugs. We performed a pharmacogenetics analysis of antipsychotic treatment response using data from 2 independent studies: a NIMH double-blind, placebo controlled inpatient cross-over trial and the CATIE study. The KCNH2 -TT associated with the 3.1 isoform was treated as a predictor variable. Treatment-associated changes in symptoms were evaluated in both groups with PANSS. Lastly, we analyzed time to discontinuation of olanzapine in the CATIE study. In the NIMH and CATIE studies, the TT genotype showed increased expression and significant improvement in positive symptoms, general psychopathology, and thought disturbance. While other genotypes showed little change. In CATIE, TT genotype was as likely to discontinue olanzapine. The effect of TT genotype on symptom changes on PANSS was greater than the effect of medication. This study provides consistent evidence of an association between SNPs in KCNH2 and short-long term clinical response to antipsychotic drugs in SZ. The 3.1 isoform modulated the therapeutic effects of antipsychotic drugs. TT genotype had a significant impact on the response to antipsychotic treatment in the NIMH cohort in both arms: those receiving placebo first and those receiving active drug first. This TT effect is noteworthy considering the small sample size and the variation in the protocol sequence of the two arms within this study. Interestingly, the significant changes in positive symptoms and general psychopathology were observed in TT risk-associated alleles at two SNPs (rs3800779 and rs1036145), the latter showing the stronger statistical significance, similar to results obtained in the smaller NIMH study. The impact of this finding in 2 independent cohorts is emphasized by the fact that these trials were performed with 2 different clinical and experimental models and different outcome measures. The effect size of the association is also notable in that the placebo-controlled NIMH study, subjects TT showed almost twice the effect size of response change compared with the other genotypes. In both NIMH and CATIE, subjects with TT genotypes predicted increased expression of 3.1, tended to have better response to antipsychotic drug therapy. The greater the expression of 3.1, the greater is the therapeutic effect. Although the penetrance of this molecular effect is not strongly predictive at the clinical symptom level, homozygosity may be a more realistic predictor of a consistent drug effect. It is easy to conclude that our pharmacogenetics results reflect the ability of antipsychotics to bind to 3.1 and the therapeutic effects are related to this effect. A cautionary note many drugs bind to hERG channels, few are antipsychotics. Drugs that affect only 3.1-lacking hERG channels might not be antipsychotic. The modulation of 3.1 leading to antipsychotic drug effects is unclear. The physiological effect of 3.1 on neuronal culture and transgenic mouse suggests that optimum therapeutic effect would not be channel blockage but restoration of normal hERG1 potassium conductance. Further research is needed on the mechanisms through which antipsychotics modulate the 3.1-related potassium channel. An alternative indirect mechanism for the relationship between KCNH2 genotype and antipsychotic drug response may be related to the firing of DA neurons. If neurons are overactive in SZ, increased 3.1 expression may drive overactivity, which is compensated by postsynaptic blockage of D2 receptors. Our study examined the potential for KCNH2 3.1 selective drugs to be novel antipsychotic therapies and encourage the pursuit of 3.1 as a potential target for development of new therapeutic agents. We also studied the effect of SNPs on working memory (WM), which integrates and manipulates information for brief periods, engages a network of prefrontal, parietal and subcortical brain regions, and is dysfunctional in SZ. Executive subprocesses of WM engage manipulation rather than simple maintenance of information, appears more vulnerable in neuropsychiatric disease, and is associated with dysfunction in DLPFC. Genetic control of these heritable brain processes have been suggested by functional SNPs influencing DA signaling which affects prefrontal activity during complex WM tasks. However, little is known about genetic control over component WM, cortico-subcortical networks, and the pharmacogenetics implications of DA-related genes on cognition in patients receiving antidopaminergic drugs. Tan et al (Brain 2012) examined predictions from basic dynamic causal models to show how genes that monitor non-D2 and D2 aspects of DA signaling in cortical and cortical-subcortical circuitries are implicated in dissociable WM maintenance and manipulation processes. In fMRI data from 46 controls, we identified differentiated effects of functional SNPs in COMT, DRD2, and AKT1 genes on prefrontal-parietal and prefrontal-striatal circuits engaged during maintenance and manipulation. Functional SNPs in COMT, DRD2, and AKT1, known to impact the biology of DA signaling are used as probes to examine these brain circuits. We also examined pharmacogenetics effects of these same SNPs on cognitive dysfunction in SZ who received anti-dopaminergic drug therapy. We found cortical synaptic DA monitored by the COMT val158met influenced prefrontal control of both parietal processing in WM maintenance and striatal processing in working memory manipulation. DRD2 and AKT1 SNPs implicated in DRD2 signaling influenced only the prefrontal-striatal network associated with manipulation. Our hypothesis-driven strategy to study component DA signaling processes in subcortical networks showed that in the context of antipsychotic drugs, the DRD2 and AKT1 SNPs altered dose-response effects of antipsychotic drugs on cognition in 111 SZ patients. We suggest that genetic modulation of these DRD2-AKT1 related circuits could influence cognitive dysfunction in psychosis and its treatment. We then examined multiple levels of AKT1 dopaminergic brain function in controls and SZ. Functional SNPs in COMT, DRD2, and AKT1 influenced working memory task-specific prefrontal control of distributed neural circuitry. Looking at cognitive deficits in SZ and antidopaminergic drug treatment, we found that the same DRD2 and AKT1 SNPs modulated the cognitive response according to antipsychotic dosage, underlying the potential therapeutic relevance of these genetic pathways. We suggest that genetic perturbation in dopaminergic signaling impact distributed prefrontal brain systems that may be relevant to individual variation in cognitive outcome of antidopaminergic treatment.